Immunotherapy Combos Are Now Standard of Care for Advanced RCC

The standard of care for treatment-naïve patients with advanced renal cell carcinoma (RCC) has shifted from a single-agent VEGF TKI to a checkpoint inhibitor plus either a VEGF TKI or a CTLA-4 inhibitor, explained David F. McDermott, MD.

For example, results of the phase III KEYNOTE-426 trial showed that the frontline combination of pembrolizumab (Keytruda) and axitinib (Inlyta) versus sunitinib (Sutent) led to a 47% reduction in the risk of death in patients with advanced RCC (HR, 0.53; 95% CI, 0.38-0.74;&#8239;P&#8239;<.0001).¹ In April 2019, the FDA approved this combination regimen as a frontline treatment for patients with advanced RCC, based on the KEYNOTE-426 findings.

Secondly, the pivotal phase III JAVELIN Renal 101 trial, demonstrated that the combination of avelumab (Bavencio) and axitinib was associated with a 31% reduction in the risk of disease progression or death compared with sunitinib in an intent-to-treat population of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.² Based on these data, the FDA approved this combination in this setting in May 2019.

In April 2018, the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline treatment for intermediate- and poor-risk patients with advanced RCC, based on results from the phase III CheckMate-214 trial. In longer follow-up of the study, the combination compared with sunitinib showed a median overall survival (OS) of not reached versus 26.6 months, respectively (HR, 0.66; 95% CI, 0.54-0.80; P <.0001).³

“By bringing PD-1/[PD-L1] into the frontline setting, we're seeing major improvements in the outcomes that patients care about, including long-term survival, for the first time in advanced kidney cancer,” said McDermott. “We're seeing deep responses, complete responses, and occasional remissions of disease, showing a true advance in the field.”

In an interview with OncLive, a sister publication of Oncology Nursing News, McDermott, a professor of medicine at Harvard Medical School as well as a staff physician and director of Biologic Therapy and Cutaneous Oncology Programs in Hematology/Oncology at Beth Israel Deaconess Medical Center, discussed developments in the frontline setting for the treatment of patients with advanced RCC.

OncLive: How has immunotherapy transformed the RCC paradigm?

McDermott: In 2015, the standard algorithm for most patients with advanced kidney cancer was a VEGF inhibitor for treatment-naïve patients, and then using a PD-1 inhibitor with nivolumab for patients who fail VEGF inhibitor. However, over the last several years, there has been a wave of new data from phase I to now phase III trials. If you combine VEGF inhibitors with PD-1 inhibitors, you can [get better outcomes] than with a VEGF inhibitor alone.

The best example of that is the KEYNOTE-426 trial, which compared pembrolizumab and axitinib with sunitinib; [the combination] showed clear benefits in objective response rate, progression-free survival, and OS. That has become a standard approach. The same could be said for the combination of axitinib and avelumab.

Another positive study was with the PD-L1 inhibitor atezolizumab (Tecentriq) and bevacizumab (Avastin). There are going to be several other trials, probably showing similar [results]. When you combine VEGF inhibitors with PD-1/PD-L1 inhibitors, you can get some improvements in outcome, including survival. That is probably because by bringing PD-1 inhibition up to the frontline setting, it tends to be most active in some of our most aggressive tumors. By giving [PD-1 inhibition] early, you are preventing those patients from dying before they get to second-line therapy.

Another approach that is now more commonly applied in a variety of other tumors is the combination of PD-1 inhibitors and CTLA-4 inhibitors that has been developed in parallel with PD-1 and VEGF inhibitor strategies. PD-1 inhibitors plus CTLA-4 inhibitors led to a very impressive result from the CheckMate-214 trial, which looked at nivolumab and ipilimumab versus sunitinib in patients with untreated metastatic disease. Those patients did much better as it relates to OS, particularly if they had intermediate- and poor-risk disease. The combination also had encouraging quality-of-life outcomes and deep responses.

The reason deep responses are something we focus on in the immuno-oncology world is because patients who have major tumor shrinkage, with 70%, 80%, or 90% of their tumors disappearing and 100% for complete responders, will have remission of their disease. We're starting to see [remissions] with these combinations at around 10% or so in CheckMate-214. That is something to build on for the future.

Where does immunotherapy fall in terms of sequencing?

Both of the PD-1 combination approaches—PD-1 inhibitors plus VEGF inhibitors and PD-1 inhibitors plus CTLA-4 inhibitors&mdash;have replaced the prior first-line therapy of VEGF inhibitor for most patients. For most of us, we're only using a single-agent VEGF TKI for people who cannot, for whatever reason, receive a PD-1 inhibitor. There are some patients who have significant autoimmune disease and they have [autoimmune disease—related] symptoms or they're receiving treatment for their autoimmune disease.

Additionally, adjuvant trials are ongoing. If practitioners have patients they might consider for those trials, they should look to see where [the trials] are open and send patients to those centers. We saw in melanoma that adjuvant immune checkpoint blockade makes a difference in relapse-free survival. That may also be the case in kidney cancer. Those trials are worth consideration for patients and practitioners.

References

1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714.

2. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med.&#8239;2019;380(12):1103-1115. doi: 10.1056/NEJMoa1816047.

3. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019;20(10):1370-1385. doi: 10.1016/S1470-2045(19)30413-9.

This article originally appeared on OncLive as, "Immunotherapy Combos Emerge as Standard Frontline Treatment in Advanced RCC."